Inhaled environmental toxins can exert effects on the lungs by altering the function of key genes. In particular, hypersensitivity immune responses to metals, such as beryllium, occur when metals modulate cytokine and growth factor expression. The consequences are granulomatous inflammation and fibrosis. Ultimately, the ability to find effective treatments for environmental lung diseases, such as chronic beryllium disease (CBD) and fibrosis, will depend upon our understanding of molecular mechanisms underlying environmentally-induced regulation of immune cell gene function. Although T lymphocytes and macrophages accumulate in the lungs of these patients, the mechanisms by which beryllium affects these cells remains obscure. The central hypothesis of this proposal is that CBD results in the generation of CD4+/CBD Th1 cells and CBD macrophages that possess abnormal, and novel, regulatory mechanisms for IFN-gamma and TNF-alpha gene expression. In CBD, beryllium exposure promulgates a cytokine amplification loop between antigen-responsive CD4+/CBD Th1 cells and CBD macrophages. Because of their novel, altered cytokine regulatory mechanisms, CBD cells over respond to cytokine signals, promoting granuloma formation. The major objectives of our study are to determine whether abnormal cytokine gene regulatory mechanisms exist in CD4+/CBD Th1 cells and CBD macrophages and to define the molecular mechanisms by which beryllium induces the production of IFN-gamma and TNF-alpha at high levels (greater than 10 ng/ml) for prolonged times (out to 168 hr) in culture. We will also determine how uncommitted T cell populations (Th0), that are seen in the stage of beryllium-sensitization that precedes CBD, are driven toward the inflammatory, pathogenic, Th1 cytokine pathway. With improved understanding of the precise cellular and molecular mechanisms that result in progressing from beryllium sensitization to CBD, we hope, in the future, to design preventive strategies to modulate disease in high risk, exposed individuals.